Bicyclic cx3cr1 receptor agonists

Abstract

Disclosed herein are novel cycloalka[b]heteroaryl compounds having CX3CR1/fractalkine receptor (CX3CR1) agonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment or prophylaxis of diseases associated with CX3CR1 receptor activity in animals, in particular humans.

1 . A compound of the following formula (I) 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof, or a salt thereof, wherein:
 n is an integer between 1 and 4, forming a 6-10-membered cycloalkyl; 
 A is chosen from phenyl and heteroaryl, optionally substituted with one or more C 1 -C 3  alkyl substituents; 
 R 1  is chosen from hydrogen and C 1 -C 3  alkyl; 
 R 2  and R 3  are independently chosen from hydrogen, phenyl, and C 1 -C 6  alkyl; 
 R 4  is chosen from 
 
       
       
         
           
           
               
               
           
         
         
           R 5  and R 6  are each independently C 1 -C 6  alkyl; 
           R 7 , R 8 , R 9 , and R 10  are independently chosen from hydrogen and hydroxyl, or is independently chosen from C 1 -C 6  alkyl and C 1 -C 6  alkyloxy, either of which is optionally substituted with methoxy; 
           p is 1 or 2; and 
           X is chosen from C, O, or NR 11  where R 11  is hydrogen or C 1 -C 3  alkyl; 
           with the proviso that if A is thiophene, n is 2 or 3, R 1  is hydrogen, and R 4  is 
         
       
       
         
           
           
               
               
           
         
       
       then either R 5  and R 6  are not both methyl, and/or R 2  and R 3  are not both methyl, and further provided that if A is thiophene, n is 2 or 3, R 1  is hydrogen, and R 4  is 
       
         
           
           
               
               
           
         
       
       then R 2  and R 3  are not hydrogen. 
     
     
         2 . The compound as recited in  claim 1 , or a stereoisomer thereof, or a salt thereof, wherein A is thiophene. 
     
     
         3 . The compound as recited in  claim 1 , or a stereoisomer thereof, or a salt thereof, wherein R 1  is chosen from hydrogen and methyl. 
     
     
         4 . (canceled) 
     
     
         5 . The compound as recited in  claim 1 , or a stereoisomer thereof, or a salt thereof, wherein R 2  and R 3  are independently chosen from hydrogen, methyl, ethyl, and phenyl. 
     
     
         6 . (canceled) 
     
     
         7 . The compound as recited in  claim 5 , or a stereoisomer thereof, or a salt thereof, wherein R 5  and R 6  are each independently C 1 -C 3  alkyl. 
     
     
         8 . The compound as recited in  claim 5 , or a stereoisomer thereof, or a salt thereof, wherein R 7 , R 8 , R 9 , and R 10  are independently hydrogen, hydroxyl, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, optionally substituted with methoxy. 
     
     
         9 . The compound as recited in  claim 5 , or a stereoisomer thereof, or a salt thereof, wherein X is chosen from C, O, or NH. 
     
     
         10 . The compound as recited in  claim 1 , or a stereoisomer thereof, or a salt thereof, wherein:
 n is a number between 1 and 4, forming a 6-10-membered cycloalkyl;   A is thiophene;   R 1  is chosen from hydrogen and methyl;   R 2  and R 3  are independently chosen from hydrogen, methyl, ethyl, and phenyl;   R 4  is chosen from   
       
         
           
           
               
               
           
         
         R 5  and R 6  are independently C 1 -C 3  alkyl; 
         R 7 , R 8 , R 9 , and R 10  are independently chosen from hydrogen, hydroxyl, C 1 -C 3  alkyl, and C 1 -C 3  alkoxy, optionally substituted with methoxy; 
         p is 1 or 2; and 
         X is chosen from C, O, or NR 11 ; and 
         R 11  is C 1 -C 3  alkyl. 
       
     
     
         11 . The compound as recited in  claim 1 , or a stereoisomer thereof, or a salt thereof, wherein A is 3-methylthiophene. 
     
     
         12 . The compound as recited in  claim 11 , or a stereoisomer thereof, or a salt thereof, wherein R 1  is chosen from hydrogen and methyl. 
     
     
         13 . (canceled) 
     
     
         14 . The compound as recited in  claim 11 , or a stereoisomer thereof, or a salt thereof, wherein R 2  and R 3  are independently chosen from hydrogen, methyl, ethyl, and phenyl. 
     
     
         15 . (canceled) 
     
     
         16 . The compound as recited in  claim 11 , or a stereoisomer thereof, or a salt thereof, wherein either:
 R 2  is hydrogen and R 3  is methyl or phenyl; or   R 2  and R 3  are both methyl or both ethyl.   
     
     
         17 . The compound as recited in  claim 16 , or a stereoisomer thereof, or a salt thereof, wherein R 2  is hydrogen and R 3  is methyl or phenyl. 
     
     
         18 . The compound as recited in  claim 16 , or a stereoisomer thereof, or a salt thereof, wherein R 2  and R 3  are both methyl or ethyl. 
     
     
         19 . (canceled) 
     
     
         20 . The compound as recited in  claim 11 , or a stereoisomer thereof, or a salt thereof, wherein R 5  and R 6  are each independently C 1 -C 3  alkyl. 
     
     
         21 . The compound as recited in  claim 11 , or a stereoisomer thereof, or a salt thereof, wherein R 7 , R 8 , R 9 , and R 10  are independently chosen from hydrogen, hydroxyl, C 1 -C 3  alkyl, and C 1 -C 3  alkoxy, optionally substituted with methoxy. 
     
     
         22 . The compound as recited in  claim 11 , or a stereoisomer thereof, or a salt thereof, wherein X is chosen from C, O, or NH. 
     
     
         23 . The compound as recited in  claim 11 , or a stereoisomer thereof, or a salt thereof, wherein
 X is chosen from C, O, and NR 11 ; and   R 11  is C 1 -C 3  alkyl.   
     
     
         24 . The compound as recited in  claim 1 , or a stereoisomer thereof, or a salt thereof, wherein:
 n is a number between 1 and 4, forming a 6-10-membered cycloalkyl;   A is 3-methylthiophene;   R 1  is chosen from hydrogen and methyl;   R 2  and R 3  are independently hydrogen, methyl, ethyl, and phenyl;   R 4  is chosen from   
       
         
           
           
               
               
           
         
         R 5  and R 6  are independently C 1 -C 3  alkyl; 
         R 7 , R 8 , R 9 , and R 10  are independently chosen from hydrogen, hydroxyl, methyl, and C 1 -C 3  alkyloxy, optionally substituted with methoxy; 
         p is 1 or 2; and 
         X is chosen from C, O, and NR 11 ; and 
         R 11  is C 1 -C 3  alkyl. 
       
     
     
         25 . A compound of the following formula (I) 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof, or a salt thereof, wherein:
 n is an integer between 1 and 4, forming a 6-10-membered cycloalkyl; 
 A is chosen from phenyl and heteroaryl, optionally substituted with one or more C 1 -C 3  alkyl substituents; 
 R 1  is chosen from hydrogen and C 1 -C 3  alkyl; 
 R 2  and R 3  are joined together via a group Y, such that R 2 —Y—R 3 , together with the carbon to which R 2  and R 3  attach, forms C 3 -C 6  cycloalkyl or C 3 -C 6  heterocycloalkyl, either of which is optionally substituted with one or more substituents chosen from hydroxyl, fluorine, and methyl; or the C 3 -C 6  cycloalkyl or C 3 -C 6  heterocycloalkyl is fused with a phenyl ring which is optionally substituted with one or more substituents chosen from hydroxyl, halogen, and C 1 -C 6  alkyl; 
 Y is chosen from C and O; 
 R 4  is chosen from 
 
       
       
         
           
           
               
               
           
         
         
           R 5  and R 6  are each independently C 1 -C 6  alkyl; 
           R 7 , R 8 , R 9 , and R 10  are independently chosen from hydrogen and hydroxyl, or is independently chosen from C 1 -C 6  alkyl and C 1 -C 6  alkyloxy, either of which is optionally substituted with methoxy; 
           p is 1 or 2; and 
           X is chosen from C, O, or NR 11  where R 11  is hydrogen or C 1 -C 3  alkyl; 
         
         with the proviso that if A is thiophene, n is 2 or 3, R 1  is hydrogen, and R 4  is 
       
       
         
           
           
               
               
           
         
       
       then R 5  and R 6  are not both methyl. 
     
     
         26 - 32 . (canceled) 
     
     
         33 . A compound chosen from any one of Examples 3, 7-9, 13, 16, 24, 42, 46-47, 54, and 67-68, or a stereoisomer thereof, or a salt thereof. 
     
     
         34 - 40 . (canceled)